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OCR for page 196
CCase Studies of the EPA's Application of the
Delaney Clause in the Tolerance-Sett~ng Process
RICHARD WILES
Case studies of nine pesticide active ingredients—fosetyl Al, benomyl,
captan, chlorobenzilate, dicamba, the ethylenebisdithiocarbamates
(EBDCs), metalaxyl, permethrin, and thiodicar~are presented. Descrip-
tions of each chemical are included along with regulatory status, special
review criteria that have been triggered, oncogenic findings and risk estima-
tion, alternative pesticides, and a discussion of issues relevant to tolerances
and the Delaney Clause (section 409~.
FOSETYL AL
Description of the Chemical
Common name: Aluminum tris (ethyl phosphonate) or fosetyl Al
Trade name: Aliette
Pesticide type: Systemic fungicide
Chemical family: Organophosphate
Year registered: 1983
Major producer: Rhone-Poulenc, under patent
Volume of use: Small
Tolerances: Fosetyl Al has section 408 tolerances of 0.1 parts
per million (ppm) for pineapples, pineapple fodder,
and pineapple forage. A recent petition for sections
408 and 409 tolerances on hops was denied. An
application for a section 408 tolerance on citrus is
pending.
196
OCR for page 197
EPA'S APPLICATION OF THE DELANEY CLAUSE 197
Regulatory Status
General-use pesticide
Special Review Criteria Triggered
Evidence of weak oncogenicity was dealt with in the registration
process.
Summary of Oncogenic Findings and Risk Estimation
The incidence of kidney tumors was statistically significant in the high
dose of one chronic feeding study. However, the high-dose feeding level
was approximately 35,000 ppm, a rate equivalent to about 4 percent of the
total diet of the test animal. Tumors termed by the EPA as of "question-
able significance" also appeared at the mid-dose level of 8,000 ppm, about
1 percent of the diet of the test animal. Alone, the mid-dose findings
would not support a finding of oncogenicity, but because of the high-dose
tumors, the pesticide was classified as oncogenic. According to informal
discussions with EPA staff, the data base for fosetyl A1 is complete and of
high caliber. In fact, the data are of such high quality that they may
actually be working against further registration of the chemical.
Fosetyl A1 has an extremely low acute toxicity. Thus, in complying
strictly with EPA guidelines instructing registrants to study the effect of
chronic feeding at the maximum tolerated dose (MTD), the registrant fed
extremely high doses of the chemical to test animals. The only oncogenic
effect observed was that mentioned above. The oncogenic risk from
dietary exposure to fosetyl A1 is calculated by the EPA at about 1 x 10-8,
or 1 in 100 million.
Tolerance and Delaney Clause Issues
A recent request for a section 3 registration on hops was denied
because it was determined that the use of fosetyl A1 on hops required a
section 409 tolerance. This tolerance could not be granted under current
law (the Delaney Clause) because residue studies showed that during
drying, fosetyl A1 concentrates to levels above the proposed 408 toler-
ances for hops. The proposed tolerance level for fosetvl A1 was 10 oom on
green hops and 15 ppm on dried hops.
,7 ~
The registrant anticipated that fosetyl A1 would make significant in-
roads into the U.S. fungicide market and quickly become a major
product. Fosetyl A1 is designed to control downy mildew in vines, as well
as numerous fungi in fruits and vegetables. Its use in these areas has
OCR for page 198
198 APPENDIX C
expanded since its introduction in Europe in 1978. It is possible that
fosetyl Al could eventually command a significant share of the U.S.
market currently occupied by more toxic or less-studied fungicides such
as the ethylenebisdithiocarbamates (EBDCs), captan, or benomyl.
For example, currently the most widely used fungicides on hops are the
EBDCs. The estimated dietary oncogenic risk from residues of EBDCs
and its metabolite ethylenethiourea (ETU) in and on hops is 1 x 10-4 to
1 X 10-5. The risk from the same use of fosetyl Al is 1 x 10-8 or less.
Were fosetyl Al to have acquired any share of the EBDC market it may
have lowered exposure to the more oncogenic EBDC and ETU residues.
BENOMYL
Description of the Chemical
Common name: Benomyl
Trade name: Benlate
Pesticide type: Systemic fungicide
Chemical family: Benzimidazole
Year registered: 1972
Major producer: Du Pont, under patent
Volume of use: Benomyl accounts for 55 percent of the $320 million
worldwide benzimidazole fungicide market. In
1984, U.S. sales amounted to approximately $60
million. In 1979 about 3 million pounds were used in
the United States on 43 food crops and 41 ornamen-
tals.
Tolerances: Benomyl has numerous section 408 tolerances and
several section 409 tolerances. New sections 408
and 409 feed additive tolerances were issued for
Benomyl in wheat, barley, and other small grains on
November 7, 1984.
Regulatory Status
A notice of Rebuttable Presumption Against Registration (RPAR, now
known as a special review) of Benomyl was initiated in 1977 because
Benomyl exceeded the risk criteria cited below; oncogenicity was not an
initial risk consideration. The Position Document (PD) 1 was published
December 6, 1977. Findings of oncogenicity were made subsequent to the
EPA's proposed decision in the PD 2/3.
A PD 4, or Notice of Determination, was published on October 12,
1982. The notice allows continued registration of all uses with protective
OCR for page 199
EPA'S APPLICATION OF THE DELANEY CLAUSE 199
clothing requirements and registrant submission of field studies to identify
residues that may enter aquatic sites after use on rice. A registration
standard for benomyl was completed in 1986.
Special Review Criteria Triggered
Reduction in nontarget species
Mutagenicity
Teratogenicity
Reproductive effects
Hazard to wildlife
Summary of Oncogenic Findings and Risk Estimation
In tests with benomyl, hepatocellular carcinomas or combined hepato-
cellular neoplasms in both male and female mice were observed at all
doses (the low dose was 500 ppm). Similar tests with a metabolite of
benomyl, methyl-2-benzimidazole carbamate (MBC), revealed combined
hepatocellular neoplasms in male mice and hepatocellular adenomas,
carcinomas, and combined hepatocellular neoplasms in female mice.
These data were received subsequent to the EPA's proposed regulatory
decision (PD 2/3) but prior to the final Notice of Determination (PD 4~.
Based on findings of oncogencity for benomyl and MBC, an oncogenic
potency factor (Q*, or extra incidence of tumors/unit dose) of 2.065 x
10-3 was determined. Multiplying projected human exposure by Q* will
estimate the 95 percent upper bound on cancer risks to humans from
lifetime exposures. Using the multistage model and residues at the
tolerance level, the upper limit of oncogenic risk to the general public via
dietary exposure to benomyl was estimated as 6.8 x 10-5. On the basis of
residue analyses, the lifetime oncogenic risk from dietary exposure to
benomyl at average expected residue levels was calculated at 7.2 x 10-6.
Tolerance and Delaney Clause Issues
The case of benomyl illustrates the relationship between the
reregistration process, tolerance reassessments, and the Delaney Clause.
Benomyl currently has section 409 feed additive tolerances on apple
pomace, grape pomace, citrus pulp, rice hulls, and tomato products.
Benomyl was granted these tolerances prior to knowledge of its
oncogencity. There is also evidence (contained in data submitted by Du
Pont to the EPA) that benomyl concentrates in orange juice, dried
apricots, plums, and grape juice. On the basis of current studies indicating
OCR for page 200
200 APPENDIX C
oncogencity, section 409 tolerance applications for these uses would
probably be denied under the Delaney Clause.2
Benomyl is the first pesticide registered before 1972 for which the EPA
will have residue data sufficient to support tolerance actions pursuant to
the Delaney Clause at the time of a major regulatory action (registration
standard). If the Delaney Clause is strictly applied, benomyl could lose
section 409 and possibly section 408 tolerances for apples, grapes, citrus,
rice, and tomatoes. These uses account for around 1.1 million pounds of
benomyl applications, or approximately one-third of all benomyl sales.
Reduction in estimated dietary oncogenic risk from revocation of these
tolerances would largely be a function of the oncogenic risk associated
with benomyl's replacements. (See Chapter 5 for further discussion of
this issue.)
Pest Resistance
A distinct feature of benomyl is that it acts systemically. Because of
this, benomyl has many more uses and does not have to be applied as
often, in as high rates, or prophylactically, as do nonsystemic fungicides
such as captan and the EBDCs. However, this characteristic has led to
the development of resistance in target fungi. According to Dr. George
Georghiou of the University of California at Riverside, of the 70 species
of fungi reported as resistant to fungicides by 1979, 69 species (84 percent)
were resistant to one material benomyl. Du Pont has recommended
lower doses per application and more precisely timed use of benomyl in
order to control the exacerbation of this problem.
To retain the advantages of benomyl use and to retard the spread of
resistance, growers often curtail use or apply benomyl in combination
with captan and/or the EBDCs. For example, Pacific Northwest apple and
pear growers use benomyl only for post-harvest disease control to reduce
the possibility of tolerant fungi strains.
Alternatives
For several pests and diseases, there are no registered substitutes for
benomyl. For example, benomyl is the only pesticide registered to control
rice blast and stem rot, which cause approximately a 12 to 15 percent loss
in rice production annually. And according to the EPA, neither cultural
practices, crop rotations, nor water management are effective in control-
ling these diseases.
The principal replacements for benomyl in fruit and vegetable produc-
tion are captan, the EBDCs, captafol, or newer systemic fungicides such
as metalaxyl or fosetyl Al. However, both captan and the EBDCs are
OCR for page 201
EPA'S APPLICATION OF THE DELANEY CLAUSE 201
under special review for oncogenic, mutagenic, and teratogenic effects,
pending the receipt of data. Although a weak oncogen, fosetyl Al has been
denied tolerances due to the Delaney Clause.
CAPTAN
Description of the Chemical
Common name: Captan
Trade names: Merpan, Orthocide, Vondcaptan, Vancide-89, and
SR-46
Pesticide type: Nonsystemic fungicide
Chemical family: Dicarboximides
Year registered: 1951
Major producers: Stauffer Chemical and Chevron Chemical produce
the technical material. There are over 600 registered
products containing captan, with registrations held
by 139 formulators and producers.
Volume of use: Approximately 9 to 10 million pounds are applied
annually.
Tolerances: Captan has more than 70 section 408 tolerances
ranging from 0.25 to 100 ppm. One section 409 food
additive tolerance is established for raisins and one
feed additive tolerance is in place for corn seed used
as animal feed.
Regulatory Status
An RPAR and PD 1 were issued on August 18, 1980. At that time the
EPA sought information on the oncogenic, mutagenic, teratogenic, and
other reproductive effects of captan.
PD 2/3 was issued June 21, 1985, in which the EPA proposed to cancel
all uses of captan on food crops unless "data are submitted that
demonstrate that actual residues are sufficiently lower than current
tolerances or that modification to application practices will sufficiently
reduce dietary risk."
Special Review Criteria Triggered
Oncogenicity
Mutagenicity
OCR for page 202
202 APPENDIX C
Summary of Oncogenic Findings
At the time of PD 1, the strongest evidence of captan's oncogenicity
was in studies by the National Cancer Institute (NCI) and Innes et al.3
These studies showed that captan can induce adenocarcinomas, adeno-
matous polyps, and mucosal hyperplasia in both sexes of mice. Two
subsequent studies for Chevron, one a high-dose (6,000 to 16,000 ppm)
and one a low-dose study (0 to 6,000 ppm), replicated the positive finding
of adenocarcinomas of the digestive tract in both sexes in mice. A
concurrent rat study, cosponsored by Stauffer and Chevron, found
statistically significant increases in combined malignant and benign kid-
ney tumors. The determination of oncogenicity has been contested by
captan's registrants. In support of its finding of oncogenicity for captan,
the EPA cites the rarity and replication of intestinal tumors in mice, and
the fact that captan is structurally similar to captafol and folpet, both of
which have demonstrated oncogenic effects in laboratory animals. Of
particular significance is the occurrence of rare intestinal tumors, includ-
ing adenocarcinomas, in chronic feeding studies of both captan and
folpet.
On the basis of this information, the EPA has assigned captan to
category B2 in their modification of the International Agency for
Research on Cancer (IARC) classification "probable human carcino-
gen." The EPA calculated the Q* (potency) factor for captan as 2.3 x
10-3.
The EPA is also requesting chronic data on tetrahydrophthalimide
(THPI), a metabolite of captan. There is some concern within the agency
that THPI may also cause tumors in laboratory animals.
Estimate of Dietary Oncogenic Risk
Using the multistage model for risk assessment, the EPA has calculated
two estimates of dietary oncogenic risk. One is based on residues of
captan at tolerance levels; the other is based on data from market basket
surveys conducted by Chevron, Stauffer, the FDA, and the Canadian
government.4
Using Food Factor consumption estimates assuming that 100 percent of
all crops with tolerances for captan are treated and that residues are at the
tolerance level, the agency estimates a dietary upper-bound oncogenic
risk of 10-3 to 10-4
When market basket survey residue figures are used, the risk is
calculated at 10-6 to 10-7. Although calculations using tolerances
probably overstate exposure and risk, the use of market basket data may
OCR for page 203
EPA'S APPLICATION OF THE DELANEY CLAUSE 203
underestimate exposure and risk because the frequency of treatment
was not stated and because both treated and untreated foods were
examined.
Tolerance and Delaney Clause Issues
Captan illustrates the difficulty of conducting risk assessments using
raw agricultural commodity (section 408) tolerances based on little or no
data. These tolerances are generally high and in many cases not supported
with valid data. They are often estimates set to accommodate the greatest
conceivable residue of the chemical. Thus, they tend to inflate risk
estimates. For example, the tolerance for apples- the major use of
captan is 25 ppm, whereas the highest residue detected in the studies
cited above5 was 0.08 ppm. The difference in these exposure estimates
could alter risk estimates for consumption of cap/an-treated apples by
three or four orders of magnitude.
Further, in many cases, pesticides registered in the 1950s and 1960s
(such as captan) have been subjected to few if any of the studies
necessary to determine whether residues concentrate in processed foods
or animal feeds. Although the residue data cited above6 indicate that
captan residues generally decline with the processing of foods, it is
possible that residues could concentrate in animal feed portions of many
crops, thus necessitating section 409 feed additive tolerances for these
crops. If tolerances were denied or revoked because of the concentration
of residues in animal feeds, significant adjustments would be required of
growers highly dependent on captan.
Other Chronic Health Risks
Captan illustrates the limitations of the Delaney Clause in reducing a
non-oncogenic dietary risk in this case a reproductive risk. The No
Observable Effect Level (NOEL) for toxic effects in reproductive
studies using captan is 12.5 mg/kg body weight/day. Using a safety factor
of 100, the allowable daily intake of captan would be 0.125 mg/kg body
weight/day. For a 60-kg person this translates into a maximum allowable
intake of 7.5 mg/day. However, using the EPA theoretical maximum
residue contributions (TMRCs) based on dietary exposure to captan
residues at the tolerance level, a person would consume 12.2 mg/kg body
weight/day of captan residues, or 63 percent more than the estimated safe
daily dose. In the absence of concurrent oncogenicity, these risks could
not be reduced by the Delaney Clause.
OCR for page 204
204 APPENDIX C
CHLOROBENZILATE
Description of the Chemical
Common name: Chlorobenzilate, or ethyl-4,4'-dichlorobenzilate
Trade name: Chlorobenzilate
Pesticide type: Acaricide
Chemical family: Organochlorine
Year registered: 1956
Major producer: Ciba-Geigy
Volume of use: Approximately 1.5 million pounds per year are
applied on citrus.
Tolerances: Chlorobenzilate has a section 408 tolerance of 5.0
ppm in citrus. There are no section 409 tolerances.
Regulatory Status
An REAR against the registration of pesticide products containing
Chlorobenzilate was issued May 26, 1976, on the basis of findings of
. . . .
Oncogen~c~ty In mice.
A PD 4, Notice of Intent to Cancel Registrations of pesticide products
containing chlorobenzilate, was issued February 13, 1979. This notice
canceled all uses except on citrus in Florida, Texas, California, and
Arizona. These remaining uses are classified as restricted and require
protective clothing during application. A registration standard was com-
pleted in 1984.
Special Review Criteria Triggered
Oncogenicity
Summary of Oncogenic Findings and Risk Estimation
Evidence of oncogenicity was found in an 18-month feeding study in
which male mice exhibited a statistically significant increase in liver
tumors when fed chlorobenzilate. An NCI study also found statistically
significant increases in total tumors and hepatocellular carcinomas in
mice. The EPA's Cancer Assessment Group classified Chlorobenzilate as
a class C "possible human carcinogen."
For most foods with tolerances, tests revealed no detectable
Chlorobenzilate residues. In these cases, a residue level of 0.1 ppm (the
level of detection) was used in calculating dietary exposure. Exceptions
were made for apples and pears because the whole fruit is consumed;
residues in these cases were set at 5.0 ppm. Because residues of 0.01-0.02
OCR for page 205
EPA'S APPLICATION OF THE DELANEY CLAUSE 205
ppm were detected in milk and beef, a 0.04-ppm residue level was used.
Using the one-hit model and these residue levels, the oncogenic risk from
dietary exposure to chlorobenzilate was calculated at 0.4 x 10-6 to 2.1 x
10-6 throughout the U.S. population.
Tolerance and Delaney Clause Issues
A potential conflict with the Delaney Clause arose during the review of
residue chemistry data for the preparation of the registration standard.
Residue studies reveal that chlorobenzilate concentrates by a factor of 5
in citrus oil. Because of the Delaney Clause, agency findings of oncogen-
icity would normally block the issuance of a section 409 tolerance and,
moreover, would draw into question the section 408 tolerance for use in
citrus. Were chlorobenzilate a new product, it would most likely have
been denied both section 408 and section 409 tolerances on citrus (see
Chapter 31. However, in this case the section 409 tolerance for citrus oil
was not issued, and the section 408 tolerance for use on citrus remains in
effect. The EPA has taken the position in this case that the oncogenic
potential of chlorobenzilate is so weak, and the consumption of citrus oil
so small, that a quantitative assessment of the oncogenic risk from
consumption of citrus oil cannot be supported by the available data.
Benefits and Alternatives
At the time of the REAR, the EPA estimated the increased total cost to
citrus growers from the cancellation of chlorobenzilate at $57 million.
Other benefits of retaining chlorobenzilate use are its application in
integrated pest management (IPM) programs and its effectiveness for
control of mites. However, some experts have argued that the EPA's
analysis exaggerated the value of chlorobenzilate in citrus production.
A 1980 study by the National Research Council7 (NRC) used
chlorobenzilate as a case study of the RPAR process. The NRC analysis
concluded that "the evidence indicates that the yield and quality of citrus
crops will not be diminished appreciably, if at all, if farmers are required
to replace chlorobenzilate treatments with some alternative" (p. 1961.
Further, the NRC calculated the added cost of these alternatives to be in
the $~$3 million range, rather than the $57 million cited by the EPA.
The principal alternative pesticides are ethion, carbophenthion, sulfur,
and dicofol. Dicofol is currently under special review and the remaining
are in the registration standard process with no evidence of oncogenic
effects. Ethion and carbophenthion are potent organophosphate insecti-
cides which present other types of risks to applicators and the environment.
OCR for page 206
206 APPENDIX C
DICAMBA
Description of the Chemical
Common name: Dicamba
Trade name: Banvel
Pesticide type: Broadleaf herbicide
Chemical family: Benzoic acid
Major producer: Sandoz
Year registered: 1967
Volume of use: 3 million pounds annually
Tolerances: Dicamba has numerous section 408 tolerances. The
establishment of a section 409 tolerance for
dicamba residues in sugarcane molasses involved
the application of the FDA "constituents policy" as
discussed below.
Regulatory Status
General-use pesticide. Registration standard was completed in 1983.
Oncogencity data are due in October 1987.
Special Review Criteria Triggered
None
Oncogenic Contaminants and the Delaney Clause
Animal studies submitted to the EPA do not show dicamba to be
oncogenic. However, these experiments were conducted at Industrial
Biotest Laboratories (IBT) and are considered invalid. Replacement tests
are scheduled for submission to the EPA in October 1987.
Studies with a contaminant of dicamba—dimethylnitrosamine
(DMNA) have shown it to be an animal oncogen. The presence of an
oncogenic contaminant in a non-oncogenic food or feed additive (pesti-
cide residue) could in theory trigger the Delaney Clause. However,
because dicamba as a whole is considered non-oncogenic in spite of the
presence of an oncogenic contaminant, the EPA employed the "constit-
uents policy" articulated by the FDA in D&C Green No. 68 to issue a
section 409 tolerance.
The FDA's constituents argument states that the safety of undesired
(oncogenic) nonfunctional constituents (in non-oncogenic substances)
should be judged under the general safety provisions of the FDC Act (not
OCR for page 215
EPA'S APPLICATION OF THE DErANEY CLAUSE 215
Metalaxyl has numerous permanent section 408
tolerances on vegetables as well as section 409
tolerances on potato and tomato products, and feed
additive tolerances for tomato and potato by-
products.
Regulatory Status
General-use pesticide with a section 3 registration. Evidence of poten-
tial oncogenicity was reviewed extensively for several years. The final
EPA decision was that metalaxyl is not an oncogen.
Special Review Criteria Triggered
Issues of oncogenicity were dealt with in the registration process.
Summary of Oncogenic Findings
Chronic rat feeding studies to support the registration of metalaxyl
were initially accepted, and the determination was made that the fungi-
cide was not an oncogen. However, questions later arose regarding the
possibility that the EPA staff had "cut and pasted" Ciba-Geigy's analysis
onto EPA letterhead to expedite their review of the chemical. Subse-
quently, a reevaluation of the data and a lab audit were ordered.
During the data reevaluation, concerns arose surrounding the appear-
ance of statistically significant parafollicular adenomas of the thyroid in
female rats at the low and middle dose, but not at the high dose, of a
two-year rat feeding study. Concurrently, the lab audit team could not
validate that the chronic feeding studies were in fact done using
metalaxyl. At this point, December 1983, all actions on metalaxyl were
halted, including tolerance approvals and emergency exemptions.
Under instructions from the registrant, the test samples were unsealed
and results showed that the studies were in fact conducted with
metalaxyl. However, upon further investigation, the EPA staff found
evidence of pheochromocytomas of the adrenal gland medulla in male
rats. Questions also appeared regarding whether the maximum tolerated
dose had been administered during the teratology and chronic feeding
studies. The toxicology branch turned the oncogenic evaluation over to
the EPA's Cancer Assessment Group which, in conjunction with other
agency staff, decided in early 1986 that metalaxyl should not be classified
as an oncogen.
OCR for page 216
216 APPENDIX C
Estimation of Risk
There was a difference of opinion among the EPA staff as to whether
metalaxyl is an oncogen. One statistical analysis of the data submitted by
Ciba-Geigy concluded that when the upper-dose finding of thyroid
adenomas in females rats was excluded, a significant dose response
relationship emerges. Using a risk estimation derived from this statistical
analysis, the EPA staff have calculated eight upper limits of oncogenic
risk from dietary exposure ranging from 2.41 per 10,000 (2.41 x 10-4) to
2.27 per 1,000 (2.27 x 10-31.
However, the validity of this interpretation is disputed within the
agency. Several staff have argued, in agreement with Ciba-Geigy, that
when the upper-dose finding is included in a calculation of oncogenic
potential, there is no dose response relationship and the incidence of this
tumor in this species in comparison to the control group is not statistically
significant.
Tolerance and Delaney Clause Issues
This example illustrates the importance of data interpretation and the
far-reaching consequences of a borderline decision on oncogenicity. The
EPA staff interpretation of data on metalaxyl ranged from classifying it as
non-oncogenic, to characterizing the dietary risk at 2.27 x 10-3.
If metalaxyl had been declared an oncogen, the Delaney Clause would
have been invoked, and metalaxyl would have been denied permanent
section 408 and section 409 tolerances in cases where residues concen-
trate in processed foods or feeds. However, because it has been declared
non-oncogenic, it will retain current tolerances and will presumably be
granted permanent tolerances for pending petitions.
Potential Uses and Alternatives
In 1979, metalaxyl was granted a conditional registration based on its
potential economic benefits to tobacco farmers in controlling blue mold
and downy mildew. Temporary tolerances exist for many other uses, but
the economic benefits of its use are not well quantified. However,
metalaxyl is generally more expensive than currently used compounds.
Pest resistance has also been a problem in isolated areas.
Currently registered alternatives to metalaxyl include the EBDCs,
captan, benomyl, captafol, and chlorothalonil. Although all of these have
chronic toxicity data indicating adverse effects usually more severe than
those associated with metalaxyl, the agency has yet to apply Delaney to
section 409 tolerances for old chemicals found to be oncogenic. Theoret-
OCR for page 217
EPA'S APPLICATION OF THE DELANEY CLAUSE 2~7
ically, metalaxyl could replace some percentage of uses of the currently
used fungicides.
In the absence of use cancellations or tolerance revocations for these
compounds, however, metalaxyl is expected to complement rather than
replace older fungicides for most crops.
PERMETHRIN
Description of the Chemical
Common name: Permethrin
Trade names: Pounce, Ambush
Pesticide type: Pyrethroid insecticide
Chemical family: Synthetic pyrethroid
Major producers: Imperial Chemicals Industries and FMC
Year registered: Conditional registration in 1978
Volume of use: Used on cotton, corn, soybeans, fruits, and vege-
tables. As a family, synthethic pyrethroids are the
fastest growing sector of the insecticide market,
with projected annual sales growth rate of 30
percent. Permethrin, however, has experienced a
recent decline in use, partially due to pest resis-
tance.
Tolerances: Numerous section 408 tolerances are established.
No section 409 tolerances have been issued be-
cause of oncogenicity and the Delaney Clause.
Regulatory Status
General-use pesticide
Special Review Criteria Triggered
Positive findings of oncogenicity in mice were dealt with in the
registration process.
Summary of Oncogenic Findings and Risk Estimation
Among six long-term mouse and rat oncogenicity studies, an increase
in malignant tumors was evident only in the lungs of female mice from
one test. For total tumors, dose response relationships were established
in two mice studies. No evidence of mutagenicity was observed in a
battery of tests including a test for DNA damage. All other oncogenicity
and mutagenicity tests were negative. After an evaluation of the weight
of toxicological evidence, the EPA concluded that at doses above 250
OCR for page 218
2 ~ ~ APPENDIX C
mg/kg body weight/day, permethrin exhibits low oncogenic potential in
mice.
The EPA concluded that although permethrin is a possible human
oncogen, the potential for oncogenic effects in humans at expected
exposure levels is "extremely low."
Delaney Clause Issues
As a result of these findings, permethrin is being regulated as an
oncogen. Most section 408 tolerances were finalized in a rule published
October 13, 1982, in the Federal Register. ]5 However, the same Federal
Register notice identified tomatoes, corn, soybeans, and apples as com-
modities in need of section 409 tolerances that would be acted upon
separately "because the results of the mouse oncogenicity studies raise
questions under the Delaney Clause." Because residues of permethrin
concentrate during processes associated with these commodities (that is,
because section 409 tolerances are required), final section 408 tolerances
for corn, soybeans, and tomatoes were delayed. No section 409 toler-
ances have been issued for these crops. All 409 tolerances have also been
denied for apples.
For tomatoes, corn, and soybeans, three different methods were used
to grant section 408 tolerances. Each case involved eliminating the need
to promulgate the associated section 409 tolerances which could not be
set because of the Delaney Clause.
TOMATOES
During processing of tomatoes, permethrin residues concentrate about
230-fold, clearly necessitating section 409 tolerances for processed to-
mato products. Because of positive findings of oncogenicity in mice, the
Delaney Clause prohibits the granting of section 409 tolerances.
Prior to the issuance of section 408 tolerances for tomatoes, no section
408 tolerance had been granted for any oncogenic pesticide in a commod-
ity where any portion of that commodity would be processed and need a
section 409 tolerance. For enforcement purposes, it was deemed impos-
sible to determine whether any portion of the treated raw agricultural
commodity would be present in any processed food or animal feed.
Permethrin was granted a section 408 tolerance, however, for use only on
"Tomatoes Grown in Florida for Final Marketing as Fresh Tomatoes."
By prohibiting the use of permethrin on tomatoes for processing, the
Delaney Clause was not invoked. Three factors were cited by the EPA to
support this decision:
1. Approximately 98 percent of all tomatoes grown in Florida are for
the fresh market.
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EPA'S APPLICATION OF THE DELANEY CrAUSE 219
2. All Florida canneries (a total of four that process tomatoes) have
signed agreements that no cannery waste from the canning of whole (not
processed) tomatoes will be used as animal feed.
3. Shipping to canneries in adjoining states is economically unfeasible.
Because no waste will be fed to animals, no section 408 tolerances for
meat, milk, or eggs were deemed necessary.
CORN
Tolerances were initially proposed for residues of permethrin and its
metabolites in or on the following raw agricultural commodities: corn
fodder at 5 ppm, corn forage at 12 ppm, and corn grain at 0.05 ppm. The
petition for corn fodder was subsequently raised to 12 ppm, whereupon
applications for both forage and fodder tolerances were dropped after
section 408 forage and fodder tolerances were granted on sweet corn.
These section 408 tolerances for sweet-corn forage and fodder carry over
to field-corn forage and fodder.
The initial tolerance petition for residues of permethrin in corn pro-
posed a use pattern for permethrin that would have allowed application of
permethrin after ears had formed and included a 30-day preharvest
interval (PHI) and a prohibition on cutting for silage within seven days of
the last application. However, residues resulting from this practice
necessitated section 409 tolerances for corn oil and soap stock.
Because the Delaney Clause will not allow section 409 tolerances for
permethrin, section 408 tolerances for permethrin in corn were denied. In
order to avoid the application of the Delaney Clause to these uses, label
restrictions were developed, supported by residue data that show that if
permethrin were not applied after ear formation, no detectable residues
(at 0.02-ppm level of detection) would remain at harvest. Lowering
residues below the level of detection (or theoretically eliminating these
residues) eliminated the need for section 409 tolerances; thus a section
408 tolerance of 0.02 ppm for permethrin in or on the raw agricultural
commodity, corn grain, was granted. Subsequently, data were submitted
to support a label change allowing application after ear formation but
prior to brown silking.
This policy also prevented the need for section 408 tolerances to cover
residues in eggs, milk, fat, and meat by-products of cattle, goats, hogs,
horses, poultry, and sheep.
SOYBEANS
Section 408 tolerances for permethrin on soybeans were also denied
pending resolution of similar Delaney issues. The need for section 409
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220 APPENDIX C
tolerances were obviated and section 408 tolerances were ultimately
granted, when residues were lowered below the level of detection through
the application of a 60-day PHI.
Discussion
One major criticism of the tolerance-setting system is that the process
is generally devoid of incentives to drive tolerances to the lowest levels
necessary for efficacious use of the product. Usually, it is only when the
Theoretical Maximum Residue Contribution (TMRC) approaches the
Acceptable Daily Intake that registrants seek to lower existing tolerances
to allow for new uses. Presumably, a tolerance lowered in this fashion
could have been lower at the time it was granted.
In the case of permethrin, the Delaney Clause provided this incentive
and clearly forced a reduction (in theory an elimination) of residues on
two major food crops corn and soybeans while at the same time
allowing these uses, and providing agriculture with new insecticides that
are generally less toxic and provide significant benefits when compared
with their major alternatives. However, where the elimination of residues
cannot be achieved, the Delaney Clause does not allow the use of
permethrin when processing will necessitate a section 409 tolerance for
that crop.
THIODICARB
Description of the Chemical
Common name: Thiodicarb
Trade name: Larvin
Pesticide type: Insecticide
Chemical family: Carbamate
Year registered: 1979
Major producer: Union Carbide, under patent
Volume of use: Not available
Tolerances: A section 408 tolerance of 2.0 ppm for thiodicarb
residues in sweet corn was established in 1984.
Sections 408 and 409 tolerances for thiodicarb and
its metabolite methomyl in or on cotton, cotton-
seed, soybeans, and soybean hulls were initially
denied under the Delaney Clause. Using the FDA's
sensitivity-of-the-method approach, these toler-
ances were finalized on October 10, 1985.
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EPA 'S APPLICATION OF THE DELANEY CLA USE 22 ~
Regulatory Status
General-use pesticide
Special Review Criteria Triggered
Positive findings of oncogenicity for acetamide, a metabolite of
thiodicarb, were dealt with in the registration process.
Summary of Oncogenic Findings and Risk Estimation
Thiodicarb has a complete data base of acceptable grade. All thiodicarb
oncogenicity studies have been submitted, and all are negative. However,
animal metabolism studies show that acetamide, an animal oncogen, is a
metabolite of thiodicarb. Four tests performed from 1955 to 1980 show
that at doses ranging from 12,500 to 80,000 ppm, acetamide is oncogenic
in test animals. Although none of these studies meet current standards for
oncogenicity testing, it is the conclusion of the agency that "the studies
collectively demonstrate that, at least under certain conditions, long-term
dietary administration of acetamide at high doses is associated with the
occurrence of liver tumors in rats." Further, "the agency believes it is
prudent to assume for present purposes that acetamide is a possible
human carcinogen."
Using the positive results in male rats from the most recent study, the
EPA calculated a level of risk from acetamide in the human diet as a
result of thiodicarb residues. This exercise employed a set of conser-
vative principles in which, among other things, the agency assumed
that
· The metabolic pathway of thiodicarb is the same as that found in test
animals, and the highest value of risk obtainable from the animal data is
applicable to humans;
· All consumed residues of thiodicarb are converted to acetamide
(which the EPA states is unlikely as suggested by the available data); and
· All cotton and soybeans grown in the United States will be treated
with thiodicarb.
On the basis of this body of evidence and these presumptions,
the EPA calculated an upper-bound estimate of total dietary oncogenic
risk from acetamide in the diet as a result of thiodicarb residues on
cotton and soybeans, of approximately 1 x 10-6. Yet, it is clear that the
agency does not believe that the dietary risks are this high. In conclud-
ing comments discussing these finds in the Federal Register, the EPA
states that because of the extremely conservative methodology em-
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222 APPENDIX C
played in the risk estimation, it "believes that the actual risk is less than
10-6. " 17
For purposes of the committee's work, it is noteworthy that the risks
involved here were insufficient to trigger a special review of thiodicarb.
As stated by the EPA in the proposed final rule:
There are no regulatory actions pending against the registration of thiodicarb. On
the basis of the available studies on acetamide and the chronic oncogenicity
studies for thiodicarb, the Agency has concluded that the human risks posed by
the use of thiodicarb on cotton and soybeans does [sic] not raise prudent concerns
of unreasonable adverse effects and that a special review under 40 CFR 162.11 is
not warranted.
Put another way, this statement means that in the opinion of the
agency, the regulatory actions surrounding thiodicarb arise entirely from
the Delaney Clause, and concern the issuance of tolerances rather than
the granting of product registration, in a case where the risk involved
would not otherwise warrant review or a delay in the issuance of such
tolerances.
TH~oD~cARs AND METHOMYL
Thiodicarb breaks down to methomyl soon after application. In fact,
the tolerances at issue here are for "thiodicarb and its metabolite
methomyl." Methomyl itself is a registered pesticide with two valid
studies showing no oncogenicity. Even though it is very likely that
acetamide is also a metabolite of methomyl, it has not yet been detected
in animal metabolism or residue studies accepted by the EPA in support
of methomyl registrations. To date, methomyl and its metabolites have
not been regulated as oncogens, nor has the Delaney Clause been invoked
against any tolerances for methomyl.
The available data do not show methomyl to concentrate during the
processing of food or animal feeds. Therefore, although section 409
tolerances have been a major issue for thiodicarb, section 409 tolerances
have not been required for methomyl. Until concentrating oncogenic
residues of methomyl and/or its metabolites are detected, the Delaney
Clause will not apply to methomyl, regardless of its chemical similarity to
thiodicarb.
Tolerance and Delaney Clause Issues
Because thiodicarb is known to concentrate in cotton seed and soybean
hulls, its use on soybeans and cotton requires section 409 feed additive
tolerances. These tolerances were initially denied because of acetamide
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EPA'S APPLICATION OF THE DELANEY CLA USE 223
oncogenicity and the Delaney Clause. As stated in the Federal Register,
the additional cancer risk from the proposed uses of thiodicarb is less than
1 X 10-6 19
According to agency sources, thiodicarb is, in a sense, a victim of the
high quality of its supporting studies. In particular, the animal metabolism
studies that detected acetamide pursued thiodicarb metabolites to an
exceptional level of detail. Had these studies not traced the metabolism of
thiodicarb so thoroughly, they might have met the EPA requirements but
not have detected acetamide as a thiodicarb metabolite. Data supporting
methomyl the major metabolite of thiodicarb and itself a registered
pesticide active ingredient have been reviewed and accepted by the
EPA, yet acetamide was not detected as a metabolite. Were acetamide
not detected as a metabolite, thiodicarb would have received section 409
tolerances and section 3 registrations on the basis of its negative
oncogenicity.
To summarize, thiodicarb needs a section 409 tolerance because it
concentrates in cottonseed and soybean hulls used as animal feed.
Thiodicarb is non-oncogenic and regardless of its concentration in feed, in
the absence of an oncogenic metabolite, the Delaney Clause would not
apply. However, thiodicarb is metabolized by livestock into acetamide,
an oncogen, which is present in meat, milk, and eggs. Thus, the EPA
interprets the Delaney Clause to prohibit the use of thiodicarb on crops
fed to animals that produce these foods.
Sensitivity-of-the-Method Procedure
Because acetamide is an animal metabolite of thiodicarb, and not
present in foods derived from soybeans and cotton treated with
thiodicarb, the setting of animal feed additive tolerances under section
409 of the FDC Act is the focal point of this exercise. Within section
409(c)~31(A) of the FDC Act is the so-called "DES proviso" which states
that the Delaney Clause
shall not apply with respect to the use of a substance as an ingredient of feed for
animals which are raised for food production, if the [Administrator] finds . . . (ii)
that no residue of the additive will be found (by methods of examination
prescribed and approved by the [Administrator] by regulation) in any edible
portion of the animal after slaughter or in any food yielded by or derived from the
living animal.
The FDA has extensively analyzed the meaning of this exception
in a document published in the March 20, 1979, Federal Register.20
Therein, the FDA concludes that the proviso should be implemented
by requiring that residues of an oncogenic compound should not be
OCR for page 224
224 APPENDIX C
allowed in the total diet of humans unless it can be verified ana-
lytically that they occur at levels less than those that, as deter-
mined by prescribed methods of extrapolation based on animal
bioassay data and a series of conservative assumptions, yield an
insignificant excess cancer risk (which the FDA sets at 1 in 1 million or
1 x 10-61.
Although this analysis of the DES proviso has not yet been formally
adopted through a final rule, the EPA employed this rationale in issuing
section 409 tolerances for thiodicarb: "For the purposes of this action,
EPA adopts the reasoning and methodology of the FDA document."
Several comments on the issuance of these tolerances criticize the EPA's
use of a procedure that has not been finalized through a formal rule
making.
Using the FDA's methodology as explained in the July 3, 1985,
proposed rulemaking for thiodicarb tolerances, the EPA calculated that
meat and poultry could contain 90 ppb acetamide residues, and the excess
lifetime cancer risk would not exceed 1 x 10-6. The agency further
estimates that at the proposed tolerance levels for thiodicarb, maximum
concentrations of acetamide residues in beef and poultry liver, which on
average contain 17 and 6 times the residues found in muscle tissue, would
be 1.8 and 0.6 ppb, respectively. For enforcement purposes (the liver will
be monitored to detect violative residues in meat) one should multiply 17
times 90 ppb to get 1,530 ppb, the maximum level of acetamide residues
allowed in liver.
The lowest levels of reliable measurement for acetamide in beef and
poultry liver, using the analytical method submitted by Union Carbide,
are 700 and 400 ppb, respectively. In the EPA's judgment, this method is
sufficient to detect violative residues in beef and poultry. Clearly, both the
level of detection and the allowable level of residues of acetamide are far
above levels expected to result from residues of thiodicarb at the
tolerances, 1.8 and 0.6 ppb.
In the cases of milk and eggs, allowable levels of acetamide of 30 and
90 ppb, respectively, were determined. In contrast, the maximum ex-
pected acetamide levels in milk and eggs resulting from thiodicarb
residues on cottonseed and soybean hulls are 0.3 and 0.07 ppb, respec-
tively. Union Carbide requested a waiver from the requirement for an
analytical method of detection because milk and egg samples purchased at
grocery stores in 11 states contained levels of 275-500 ppb acetamide for
milk, and 75-350 ppb acetamide for eggs far above anticipated maxi-
mum residues from use of thiodicarb as well as those equivalent to a risk
of 1 x 10-6 (30 and 90 ppb). Because EPA tests also found acetamide
residues to be ubiquitous, the requirement for an analytical method was
waived.
i'
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EPA'S APPLICATION OF THE DELANEY CLAUSE 225
NOTES
1. U.S. Environmental Protection Agency. 1982. Benomyl Fact Sheet. Washington, D.C.
2. Holder, J. A. 1980. Memorandum to C. Chaisson, U.S. Environmental Protection
Agency, regarding correction of worst-case dietary exposure to benomyl in the United
States for percent crop tracked and direct sampling of selected crops in a Du Pont
market booklet survey. U.S. Environmental Protection Agency, Washington, D.C.
3. Environmental Protection Agency Rebuttable Presumption Against Continued Regis-
tration of Products Containing Captan. 1980. Federal Register 45(No. 161, August 18):
54938-54985.
4. U.S. Environmental Protection Agency. 1985. Captan Special Review Position Docu-
ment 2/3. Washington, D.C.: U.S. Environmental Protection Agency. Sec. 2, pp. 91-92.
5. Ibid.
6. Ibid.
7. National Research Council. 1980. Regulating Pesticides. Washington, D.C.: National
Academy Press.
Federal Register 47(April 2, 1982): 14136.
9. Federal Register 49(December 5, 1984):47482.
10. Environmental Forum. December 1984. Pesticides—Changing the Way EPA Does
Business, pp. 17-18.
11. U.S. Environmental Protection Agency. 1982. Ethylenebisdithiocarbamates. Decision
Document, Office of Pesticides and Toxic Substances. Washington, D.C., p. I-11.
12. Ibid.
13. Ibid., p. I-38.
14. Ibid., p. I-39.
15. Federal Register 47(0ctober 13, 1982):45008.
16. Federal Register 50(No. 128):27453.
17. Federal Register 50(No. 197):41342.
18. Federal Register 50(July 3, 1985):27464.
19. Federal Register 50(No. 197):41342.
20. FederalRegister44(March20, 1979):17020.
21. Ibid.
Representative terms from entire chapter:
dietary exposure
